1. The Invention
This invention relates to 4,5-dihydro-2-alkoxycarbonylamino-4-(phenyl and mono- and di-substituted phenyl)-imidazoles, pharmaceutically acceptable salts thereof and methods of preparing such compounds. In another aspect, this invention relates to 4,5-dihydro-2-alkoxycarbonylamino-4-(methylenedioxyphenyl)-imidazoles, pharmaceutically acceptable salts thereof and methods of preparing such compounds.
This invention also relates to methods and compositions of treating or palliating abnormal conditions related to the central nervous system, in mammals, e.g. depression, anxiety, convulsions, centrally-induced skeletal muscle spasm and spasticity by the administration of the compounds of the invention.
2. The Prior Art
A general discussion of psychotic disorders and the use of psychotropic drugs can be found in The Pharmacological Basis of Therapeutics, 4th Edition, L. S. Goodman and A. Gilman eds., McMilland Co., New York (1970).
In 1973 a group of 2-amino-4-aryl-2-imidazolines were described in the Journal of Medicinal Chemistry, Vol. 16, No. 8, page 901 (1973), primarily as anti-hypertensive agents but were also tested for a number of other biological activities including whether the compounds reversed or prevented the effect of reserpine on mice. This publication indicated that some 2-amino-4-aryl-2-imidazolines prevented the effect of reserpine-induced ptosis, induced by the administration of 2 mg/kg of reserpine, whereas others were inactive in this test.
It is known that certain 4- or 5-aryloxazoles which are substituted at the 2-position with an acylamino, hydrocarbon aminocarbonylamino or alkoxycarbonylamino have antiinflammatory, CNS or anti-bacterial activity respectively. See, for example, Lilly's Great Britain Pat. Nos. 1,264,258 and 1,327,042 and Ajinomoto's Japanese Pat. No. 7134422. It is also known that certain 5-aryl-4-oxo-2-imidazolidinylidene ureas are useful as antisecretory agents and CNS depressants. See Belgian Pat. No. 821,099 to McNeil Labs. These compounds are entirely different from the compounds of this invention.
In contrast to the compounds described in the prior art, the compounds of the present invention are 2-alkoxycarbonylamino-4-phenyl-2-imidazolines, a number of which have been found to exhibit the ability to reverse hypothermia and ptosis induced by 5 mg/kg reserpine in laboratory animals; two well accepted assay methods for identifying compounds of clinical utility in the treatment of endogenous depression. In addition, a number of compounds of the present invention display mild tranquilizing and/or sedating properties in behavorial assays, and/or they have the ability to protect animals against various kinds of experimentally induced, convulsive seizure states and further exhibit centrally acting skeletal muscle relaxant properties. This spectrum of activities indicates that the compounds of this present invention possess a unique activity profile unlike that of any currently known psychotropic agents.